Medicinal compositions having an antalgic action



MEDICINAL COMPOSITIONS HAVING AN ANTALGIC ACTION Filed July 27, 1962 United States Patent M 3,172,809 MEDICINAL COMPOSITIONS HAVING AN ANTALGIC ACTION Jean Montandraud, Casablanca, Morocco, assignor to Societe dApplications Chimiques, dEtudes & de Recherches (S.A.C.E.R.), Monte Carlo, Monaco Filed July 27, 1962, Ser. No. 212,996 Claims priority, application Great Britain Oct. 6, 1961 4 Claims. (Cl. 16765) The present invention relates to new medicinal preparations or compounds having an antalgic or analgesic action.

The present invention consists of a new compound which is the result of the association of two known compounds which separately have limited antalgic action values, the total value of which, however, is below the antalgic action value of the new chemical compound.

The medicament according to the invention results from the association, with acetylsalicylic acid, of a small proportion of a thiamine derivative such as diacetylthiamine, which improves to an unexpected degree the antalgic action of the former.

By thiamine derivative is intended a compound selected from the group of the thiaminic compounds the ring of which is open and blocked in this state. Such blocking can be the result of the formation of a dithioalkyl derivative or of an ester, i.e. a diester (diarylthiamines), the primary alcoholic group of the molecule being also esterified. For convenience it will be easier in the following to refer to diacetylthiamine, but it is well understood that the invention embraces quite generally all the associations of acetylsalicylic acid with any member of the aforementioned group, such as dibenzoylthiamine or dithiopropylthiamine, thiamine itself not belonging to this group and being excluded from the invention.

The antalgic action of acetylsalicylic acid or aspirin is universally known, and it is recognized that this action increases with higher doses; it is however also recognized that the use of aspirin results in non-negligible side effects, and this imposes some limitation to the doses administered safely, so that it should be noted that there exists restricted therapeutic doses for aspirin.

Moreover it is known that diacetylthiamine and similar compounds have only a very slight and non durable antalgic action.

Now it has been surprisingly discovered that the addition to such usual therapeutic dose of aspirin, resulting by itself alone in a known limited antalgic action, of a limited proportion, of about by weight, of diacetyl thiamine or of a similar compound, with no antalgic action at this dose, results in a very remarkable increase of the degree, of the rapidity and of the duration of the antalgic action of aspirin without any of the side-effects which would appear if the corresponding dose of aspirin alone had been administered.

This result is all the more surprising in the light of the fact that the addition of thiamine itself to aspirin under similar conditions, produces practically no effect.

It is important to note that this result was obtained from clinical observations carried out on many hundreds of patients who underwent tests of great value (Deneau, Wand and Gowdey, Can. J. Med. Sci. 31, 1953-387-93), the experimental process of which was as follows:

The stimulus applied was the pressure provided by arm band of blood pressure apparatus: this was placed on the upper third portion of the leg, its exact position was marked with a dermographic pencil. In order to obtain results that could be compared, the subject was made to sit on the same chair with his foot resting on the 3,172,809 Patented Mar. 9, 1965 floor between marks; thus the angle of the foot in regard to the leg was the same each time.

The subjects were all aged 18 to 30 and clinically healthy.

They fasted for six hours and did not take any liquid for at least 24 hours.

First the threshold of provoked pain was determined on the normal subject. In the course of this first test, subjects on whom the threshold of pain varied to an appreciable extent, were eliminated. 98 readings on 24 subjects were taken in order to establish the threshold which revealed itself to be l85.56:3.09 mm. Hg.

Lastly, for 12 subjects, namely 11 men and 1 woman, research was carried out on each in order to determine the pain threshold after the consumption of capsules of similar appearance which contained:

(a) Placebo: Lactose 800 mg.

([1) Aspirin 700 mg.+Lactose 100 mg.

(0) Diacetylthiamine (DAT) 100 mg.+Lactose 700 mg. (d) Aspirin 700 mg.'+DAT 100 mg.

i.e. two tablets that were voluntarily placed inside the cupulae of a capsule identical to the preceding capsules in order to avoid possible psychological interference in the course of the experiment.

The various capsules were administered indiscriminately and duplicate readings were taken for each subject.

Thus the threshold of pain was determined at intervals of a half-hour, one hour and three hours after consumption of the capsule, excepting for the association under sub paragraph (d) for which the reading had to be continued until the end of the fifth hour.

Every care was taken to ensure satisfactory psychic relaxation and to divert the attention of the subject away from the manometer so as to avoid their reading it, thereby ensuring that pain took the subject by surprise instead of him expecting it.

598 readings of the pain threshold were thus carried out.

The alterations that the drugs under study brought to the normal pain threshold were expressed in percentage in comparison to the normal threshold.

Attention is drawn to the small variations in the individual figures which appear to strengthen the value of the Deneau test for this type of experiment.

(a) Placebo The absorption of lactose does not alter in a significant manner the pain threshold (max. 2.65:4.18 percent).

(b) Aspirin at 700 mg.

The absorption of aspirin (700 mg.) increases significantly the threshold of pain (the maximum action is reached at the end of an hour with 2l.58:2.0l percent).

For the placebo and aspirin the above figures of the tests agree substantially with those found by Deneau as well as with those found by Truchaud and Garraud ("Anesthesie-Analgsie, 1958, XV 340-350), while taking into account the fact that the doses they used were of half strength.

(0) Diwcetylthiamine at 100 mg.

Here again, the increase in the pain threshold is significant although it is less than that due to aspirin, viz. l3.64i5.00 percent.

It should be added that to the best of our knowledge and belief this is the first time that the analgesic action of a derivative of thiamine has been demonstrated objectively.

(d) Aspirin4+diacetylthiamine700 mg.+100 mg. The dose administered orally to each subject corresponded to twocapsules; it therefore contained as much aspirin and- DAT for each of the preceding tests.

Half an hour after this dose was administered, the pain threshold rose by 18.97 percent; it reached its peak (31.50 percent). atthe end of an hour, then declined slowly from the second to the. fourth hour (28.47- 20.83-.-13.'53%) and found its normal value at the end of the fifth hour.

For the:purpose of comparison, the same test has been carried out in view of appreciating the eventual antalgic action .of thiamine alone and in association with aspirin; the: drugs being also administered in similar capsules, all the conditions being the same.

These tests showedthat:

The thiamine alone has no antalgic action whatsoever, the results being .the same as those obtained with the placebo.

The association of thiamine-i-aspirin has an antalgic action'not'higher than aspirin alone.

These results show that the diacetylthiamine and the similar thiamine compounds with an open ring have a distinct and unique activity in their association with aspirin, and that thiamine itseif has not this activity. Such potentializing activity appears therefore with no relation with the B activity of thiamine.

The above reported results are still more apparent from the curves. of the attached drawing, which illustrates the increase .(in percent) of the pain threshold, in function of time (in hrs.) after administration, respectively:

Curve 1: Curve 2: Curve 3: Curve 4:

Curve 5: vitamin B alone (100 mg.) Curve 6: vitamine B -l-aspirin (700 mg.)

The curves show for each measurement the average value and the typical error.

I claim:

1. A pharmaceutical composition consisting essentially of 700 mg. of acetlysalicylic acid and 100 mg. of diacetylthiamine.

2. A methodfor reducing pain in patients which comprises orally administering to said patients an antalgic composition consisting essentially of 700 mg. of acetylsalicylic acid and 100 mg. of diacetylthiamine.

3. A pharmaceutical composition consisting essentially of acetylsalicylic acid and diacetylthiamine, the diacetylthiamine being present in an amount at least 10% by Weight.

4. A method of reducing pain in patients which comprises orally administering to said patients an antalgic composition consisting essentially of a mixture of acetylsalicylic acid and diacetylthiamine, the latter being present in an amount at least 10% by weight.

' References Cited by the Examiner UNITED STATES PATENTS 2,752,348 6/56 Matsukawa 260-2565 2,833,768 5/58 Fujiwara 260-256.5

OTHER REFERENCES Wilson: American Drug Index, 1961, p. 723.

JULIAN S. LEVITT, Primary Examiner.

MORRIS O. WOLK, LEWIS GOTTS, Examiners. 

1. A PHARMACEUTICAL COMPOSITION ESSENTIALLY OF 700 MG. OF ACETYLSALICYLIC ACID AND 100 MG. OF DIACETYLTHIAMINE. 